Radiation therapy is utilized to treat over 50% of all patients with cancer. Although radiation therapy plays a critical role in curing some cancer patients and palliating others, a fundamental gap in improving the efficacy of radiation therapy exists because the mechanisms by which radiotherapy controls tumors and causes side effects remain poorly understood. Previously, we used Cre recombinase to generate mouse models to study mechanisms of acute and late effects of radiation. Here, we will apply these models to dissect the molecular mechanism regulating the alpha/beta ratio, which is frequently used in the clinic to select radiation doses and schedules for patients, but currently lacks a molecular rationale. Moreover, we have used Cre recombinase to develop genetically engineered mouse models of soft tissue sarcoma and lung cancer to study radiation biology. To study the complex interactions of tumor stroma and parenchymal cells during radiation therapy, we have recently generated novel strains of genetically engineered mice in which primary cancers can be generated with Flp recombinase. In this system, Cre recombinase can still be utilized to modify genes specifically in the tumor stroma. Utilizing Flp and Cre recombinases (i.e. dual recombinase technology) to study the tumor microenvironment's impact on radiation therapy is highly innovative because primary cancers can be initiated with one recombinase, while the other recombinase can be utilized to specifically modify stromal cells. In addition, we have recently generated novel genetically engineered mice in which Flp recombinase activates CreER expression. Therefore, with our novel system Flp initiates tumorigenesis and the tumor cells express CreER so that tamoxifen can modify genes specifically in tumor cells after the tumor has developed. We will use this system to study cell autonomous mechanisms that regulate tumor response to radiation therapy. Advancing the care of cancer patients with discoveries in radiation biology is ambitious, but with our track record of productivity and high impact research, we are poised to use our innovative mouse models to make discoveries that will lay the foundation for novel approaches to improve the efficacy of radiation therapy.